Abstract Mycobacterium tuberculosis kills approximately 1.5 million people annually. It has long been observed that mycobacterial granulomas can be extensively vascularized, but the functional consequences of this vascularization have not been fully examined. Using a zebrafish mycobacterial infection model that recapitulates important aspects of human mycobacterial granulomas, we found that granuloma-induced angiogenesis coincides with the generation of local hypoxia and transcriptional induction of the canonical pro- angiogenic molecule Vegfa. Interception of this pathway with clinically used inhibitors resulted in reduced burden and improved outcome. Building on our preliminary data that suggest a role for the VEGF pathway and the bacterial lipid trehalose dimycolate, we will define the cellular and molecular mechanisms by which pathogenic mycobacteria promote the pro-angiogenic environment of mycobacterial granulomas to facilitate their own growth, dissemination and survival. We also will probe the role of a parallel canonical angiogenic signaling pathway ? the angiopoietin/Tie2 pathway ? for which we have identified a novel host-directed drug that we have shown to be effective in reducing mycobacterial burden in zebrafish. Finally, we will build on our recent data showing induction of these pathways in human granuloma specimens and probe the functional effects of human genetic variants in mycobacterial infection. Overall, this proposal tests the hypothesis that, in a striking parallel to tumor biology, the interplay of angiogenesis, hypoxia and compromised vasculature contributes to mycobacterial pathogenesis. Ultimately, the modulation of these pathways may provide new strategies for host- directed therapies for tuberculosis.